The vasculature associated with fast proliferating solid tumors is abnormal, which limits efficient oxygen supply and renders the tumor tissue hypoxic. The presence of hypoxic areas in solid cancers has been correlated with resistance to chemotherapy and radiation treatment. Intratumoral hypoxia induces hypoxia inducible factors (HIFs), transcription factors that activate genes controlling mechanisms such as glycolysis, erythropoiesis, angiogenesis, and cell motility, which can benefit the survival of cancer cells. HIFs can also influence the self-renewal of cancer stem-like cells (CSCs) and be activated in response to growth factors, oncogenes, and inactivation of tumor suppressor genes.
HIFs are heterodimeric protein complexes, composed of HIF-α and HIF-β subunits, which then associate with cofactors such as p300 and CBP to form active transcription factors. The regulation of HIFs largely occurs at the protein level, and is dependent upon the synthesis and stability of the HIF-α subunits. Under normoxia, HIF-α subunits are hydroxylated at proline residues by oxygen-dependent prolyl hydroxylases (PHDs), which mediates recognition by the Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex and rapid degradation by the proteasome. Under hypoxia, HIF-α subunits are stabilized due to the inhibition of proline hydroxylation, and a functional HIF transcriptional complex is assembled, translocates to the nucleus, and transcribes genes that contain DNA sequences called hypoxia response elements (HREs). Elevated levels of HIF-1α have been correlated with poor prognosis of patients with glioblastoma (GBM), breast, pancreatic, colon, and metastatic lung cancers.
Hypoxic tumor and HIF-1 have been evaluated as targets for anticancer therapy using a variety of approaches. While the differential function of HIF-1 and HIF-2 isoforms is still under investigation both are associated with brain cancer stem-like cells, and most studies suggest that one or both isoforms need targeting, depending on tumor and cancer type. Therefore, tumor cells overexpressing HIF represent an important target for antitumor therapy.
A number of existing chemotherapeutics can alter HIF activity as a result of their pleiotropic effects, including 2ME2, 17-DMAG, 17-AAG, camptothecin, PX-478, and YC-1. Most of the agents studied affect HIF indirectly via the inhibition of microtubule polymerization, Hsp90, topoisomerase I, thioredoxin 1, or other unknown mechanisms. A search for more specific inhibitors used a screen targeting the interaction of HIF with the key transcriptional coactivator p300. A recent study suggests that acriflavine, an antitrypanocidal, antibacterial, and antiviral agent interferes with HIF-1α and -1β dimerization and possibly other signaling pathways such as NF-κB. It is also desirable to develop several agents that can interfere with HIF transcription in different ways so that we are prepared for the development of tumor resistance against single targeted sites.